JPWO2015178343A1 - siRNA細胞内送達のための脂質膜構造体 - Google Patents
siRNA細胞内送達のための脂質膜構造体 Download PDFInfo
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- JPWO2015178343A1 JPWO2015178343A1 JP2016521092A JP2016521092A JPWO2015178343A1 JP WO2015178343 A1 JPWO2015178343 A1 JP WO2015178343A1 JP 2016521092 A JP2016521092 A JP 2016521092A JP 2016521092 A JP2016521092 A JP 2016521092A JP WO2015178343 A1 JPWO2015178343 A1 JP WO2015178343A1
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Abstract
Description
で表される脂質化合物又はその塩が提供される。
リン脂質及びリン脂質誘導体としては、例えば、ホスファチジルエタノールアミン、ホスファリジルコリン、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジルグリセロール、カルジオリピン、スフィンゴミエリン、セラミドホスホリルエタノールアミン、セラミドホスホリルグリセロール、セラミドホスホリルグリセロールホスファート、1,2-ジミリストイル-1,2-デオキシホスファチジルコリン、プラスマロゲン、ホスファチジン酸などを挙げることができ、これらは1種又は2種以上を組み合わせて用いることができる。これらリン脂質における脂肪酸残基は特に限定されないが、例えば、炭素数12〜20の飽和又は不飽和の脂肪酸残基を挙げることができ、具体的には、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、リノール酸などの脂肪酸由来のアシル基を挙げることができる。また、卵黄レシチン、大豆レシチンなどの天然物由来のリン脂質を用いることもできる。
飽和又は不飽和の脂肪酸としては、例えば、パルミチン酸、オレイン酸、ステアリン酸、アラキドン酸、ミリスチン酸などの炭素数12〜20の飽和又は不飽和の脂肪酸が挙げられる。
例えば、本発明の脂質膜構造体の核内移行を促進するために、例えば、脂質膜構造体を3糖以上のオリゴ糖化合物で表面修飾することもできる。3糖以上のオリゴ糖化合物の種類は特に限定されないが、例えば、3個ないし10個程度の糖ユニットが結合したオリゴ糖化合物を用いることができ、好ましくは3個ないし6個程度の糖ユニットが結合したオリゴ糖化合物を用いることができる。
(1) (9z,12z)-octadecadien-1-ol
4℃に冷却したテトラヒドロフラン(THF)190 mLに、水素化リチウムアルミニウム2.73 g(72 mmol)を懸濁した。そこへリノール酸10 g(36 mmol)を滴下し、10分間撹拌した。その後、オイルバスで加熱しながら一晩還流した。これを冷却した後、1 mol/Lの水酸化ナトリウム水溶液100 mLを加えて反応を停止させた。次に、酢酸エチル100 mLを加えて希釈した後、濾過し、濾液を飽和炭酸水素ナトリウム水溶液を用いて洗浄した。続いて、有機層を回収して、そこに無水硫酸ナトリウムを加えて脱水した。これを濾過した後、ロータリーエバポレーターを用いて溶媒を留去し、粗生成物を得た。粗生成物をシリカゲルクロマトグラフィー{溶離溶媒;ヘキサン:酢酸エチル(連続勾配)}に供することにより精製して、(9z,12z)-octadecadien-1-ol 8.68 g(32.6 mmol)を無色オイルとして得た。収率は91%であった。
(9z, 12z)-octadecadien-1-olのプロトン核磁気共鳴(1H NMR;500 MHz)データ
δ=0.88 (t, 3H), 1.25-1.36 (m, 16H), 1.53-1.58 (m, 2H), 2.02-2.06 (m, 4H), 2.76 (t, 2H), 3.62 (t, 2H), 5.29-5.40 (m, 4H).
(9z,12z)-octadecadien-1-ol 8.68 g(32.6 mmol)を100 mLのジクロロメタンに溶解した後、N,N-dimethyl-4-aminopyridine(DMAP)366 mg(3.26 mmol)、triethylamine(TEA) 6.8 mL(48.9 mmol)を加えた。続いて、滴下ロートを用いて、50 mLのジクロロメタンで希釈したmethanesulfonyl chloride 3.03 mL(39.1 mmol)を滴下し、室温で一晩撹拌した。反応液を回収して、飽和炭酸水素ナトリウム水溶液を用いて洗浄した。続いて、有機層に無水硫酸ナトリウムを加えて脱水した。これを濾過した後、ロータリーエバポレーターを用いて溶媒を留去し、粗生成物を得た。粗生成物をシリカゲルクロマトグラフィー{溶離溶媒;ヘキサン:酢酸エチル(連続勾配)}に供することにより精製して、(9z, 12z)-octadecadien-1-methanesulfonate 10.64 g(30.9 mmol)を無色オイルとして得た。収率は95%であった。
(9z, 12z)-octadecadien-1-methanesulfonateのプロトン核磁気共鳴(1H NMR;500 MHz)データ
δ=0.88 (t, 3H), 1.06-1.18 (m, 18H), 1.70-1.90 (m, 2H), 2.00-2.19 (m, 4H), 2.79 (t, 2H), 3.06 (s, 3H), 4.20 (t, 2H), 5.21-5.42 (m, 4H).
(9z,12z)-octadecadien-1-methanesulfonate 10.64 gを140 mLのジエチルエーテルに溶解した後、magnesium bromide ethyl etherate 16.0 g(61.8 mmol)を加え、室温で一晩撹拌した。反応液を回収して、100 mLの飽和炭酸水素ナトリウム水溶液を用いて洗浄した。続いて、有機層に無水硫酸ナトリウムを加えて脱水した。これを濾過した後、ロータリーエバポレーターを用いて溶媒を留去し、粗生成物を得た。粗生成物をシリカゲルクロマトグラフィー{溶離溶媒;ヘキサン:酢酸エチル(連続勾配)}に供することにより精製して、18-bromo-octadeca-(6z,9z)-diene 8.85 g(26.9 mmol)を無色オイルとして得た。収率は87%であった。
18-bromo-octadeca-(6z, 9z)-dieneのプロトン核磁気共鳴(1H NMR;500 MHz)データ
δ=0.88 (t, 3H), 1.27-1.46 (m, 18H), 1.80-1.88 (m, 2H), 2.00-2.09 (m, 4H), 2.77 (t, 2H), 3.40 (t, 2H), 4.20 (d, 2H), 5.29-5.41 (m, 4H).
1.5 mLのジエチルエーテルに18-bromo-octadeca-(6z,9z)-diene 0.50 g(1.52 mmol)を溶解し、削り屑状マグネシウム609 mg(25.1 mmol)を加え、続いてヨウ素1欠片を加えた。室温で10分間静置した後、オイルバスで45℃に加熱しながら撹拌し、6 mLのジエチルエーテルに溶解した18-bromo-octadeca-(6z, 9z)-diene 5.0 g(15.2 mmol)を滴下した。45℃で1時間反応させた後、室温に冷却した。続いて、δ-バレロラクトン300 μL(3.23 mmol)を添加し、室温で1時間反応させた。次に、4℃に冷却し、濾過した後、濾液を飽和炭酸水素ナトリウム水溶液で洗浄した。続いて、有機層に無水硫酸ナトリウムを加えて脱水した。これを濾過した後、ロータリーエバポレーターを用いて溶媒を留去し、粗生成物を得た。粗生成物をシリカゲルクロマトグラフィー{溶離溶媒;ヘキサン:酢酸エチル(連続勾配)}に供することにより精製して、4-[(9z, 12z)-octadecadienyl]-(13z, 16z)-tricosadien-1,4-diol 1.64 g(2.73 mmol)を無色オイルとして得た。δ-バレロラクトンからの収率は85%であった。
4-[(9z,12z)-octadecadienyl]-(13z,16z)-tricosadien-1,4-diolのプロトン核磁気共鳴(1H NMR;500 MHz)データ
δ=0.88 (t, 6H), 1.25-1.1.46 (m, 46H), 2.02-2.06 (m, 8H), 2.77 (t, 4H), 3.66 (t, 2H), 5.30-5.40 (m, 8H).
4-[(9z, 12z)-octadecadienyl]-(13z, 16z)-tricosadien-1,4-diol 301 mg(0.50 mmol)を5.0 mLのジクロロメタンに溶解し、DMAP 6.11 mg(0.05 mmol)とTEA 83.6 μL(0.60 mmol)を加え、続いてp-toluenesulfonyl chloride 95.3 mg(0.50 mmol)を加えた後、室温で一晩撹拌した。続いて、反応液にシリカゲルを加え、ロータリーエバポレーターを用いて溶媒を留去した。その後、シリカゲルクロマトグラフィー{溶離溶媒;ヘキサン:酢酸エチル(連続勾配)}に供することにより精製して293 mg(0.39 mmol)を無色オイルとして得た。収率は78%であった。
4-[(9z, 12z)-octadecadienyl]-1-p-toluenesulfonyl-(13z, 16z)-tricosadien-4-olのプロトン核磁気共鳴(1H NMR;500 MHz)データ
δ=0.88 (t, 3H), 1.25-1.49 (m, 46H), 2.03-2.05 (m, 8H), 2.44 (s, 3H), 2.77 (t, 4H), 4.03 (t, 2H), 5.31-5.39 (m, 8H), 7.34 (d, 2H), 7.78 (d, 2H).
1-N,N-dimethylamino-4-[(9z, 12z)-octadecadienyl]-(13z, 16z)-tricosadien-4-olのプロトン核磁気共鳴(1H NMR;500 MHz)データ
δ=0.87 (t, 6H), 1.23-1.40 (m, 46H), 2.02-2.07 (m, 8H), 2.26 (s, 6H), 2.33 (t, 2H), 2.77 (t, 4H), 5.31-5.39 (m, 8H).
YSK12-MENDをアルコール希釈法により調製した。総脂質量が505 nmolとなるようにYSK12、1-パルミトイル-2-オレイル-sn-グリセロ-3-ホスホエタノールアミン(POPE)、コレステロール(Chol)、1,2-ジミリストイル-sn-グリセロール、メトキシポリエチレングリコール2000 (DMG-PEG 2000)を含む90% t-ブタノール溶液400 μlに撹拌下でsiRNA 600 pmolを含む水溶液を200 μl添加した。さらに撹拌下で20 mMのクエン酸緩衝液を2 ml添加し、続いて3.5 mlのPBSを添加後に限外ろ過を行った。
GAPDH silencer siRNA又はcontrol silencer siRNAを封入したYSK12-MENDを例2と同様の方法で調製した。12ウエルプレートにOPTI-MENDに懸濁した細胞を6×105cell/wellとなるように播種し、さらにsiRNAの終濃度が3、10、及び30 nMになるようにYSK12-MEND又はLipofectamineRNAiMAXを加えた。2時間培養後、血清入り培養培地を添加して22時間培養した。その後、細胞を回収しリアルタイムRT-PCR法によりmRNA量を評価した。結果を図12に示す。LipofectamineRNAiMAXと比較してYSK12-MENDではより効率的に遺伝子ノックダウンが達成できることが示された。
GAPDH silencer siRNAを封入したYSK12-MENDを例2と同様の方法で調製した。12ウエルプレートにOPTI-MENDに懸濁した細胞を6×105 cell/wellとなるように播種し、さらにsiRNAの終濃度が1及び3 nMになるようにYSK12-MENDを加えた。2時間培養後、血清入り培養培地を添加して22時間培養した。その後、細胞を回収しリアルタイムRT-PCR法によりmRNA量を評価した。結果を図13に示す。例3におけるTHP-1と同レベルの効率的な遺伝子ノックダウンが達成できることが示された。
Claims (8)
- 下記の式(I):
で表される脂質化合物又はその塩。 - nが4、mが7〜9の整数であり、pが3〜5の整数であり、R3及びR4がそれぞれ独立にC1-4アルキル基である請求項1に記載の脂質化合物又はその塩。
- R1及びR2が同一であり、nが4、mが8であり、pが4であり、R3及びR4がメチル基である請求項1に記載の脂質化合物又はその塩。
- 細胞内にsiRNAを送達するための脂質膜構造体の脂質成分として用いるための請求項1ないし3のいずれか1項に記載の脂質化合物又はその塩。
- 細胞内にsiRNAを送達するための脂質膜構造体であって、siRNAが内部に封入されており、かつ脂質成分として請求項1ないし3のいずれかに記載の脂質化合物を含む脂質膜構造体。
- リポソームである請求項5に記載の脂質膜構造体。
- 樹状細胞において標的遺伝子をノックダウンするために用いる請求項5又は6に記載の脂質膜構造体。
- 患者から樹状細胞を分離・採取し、インビトロで樹状細胞の細胞内にsiRNAを導入した後、標的遺伝子がノックダウンされた樹状細胞をその患者に投与する免疫療法において、樹状細胞における標的遺伝子をノックダウンするために用いる請求項7に記載の脂質膜構造体。
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